Beyond ‘significance’:Principles and practice of the analysis of credibility

The inferential inadequacies of statistical significance testing are now widely recognized. There is, however, no consensus on how to move research into a ‘post p < 0.05’ era. We present a potential route forward via the Analysis of Credibility, a novel methodology that allows researchers to go beyond the simplistic dichotomy of significance testing and extract more insight from new findings. Using standard summary statistics, AnCred assesses the credibility of significant and non-significant findings on the basis of their evidential weight, and in the context of existing knowledge. The outcome is expressed in quantitative terms of direct relevance to the substantive research question, providing greater protection against misinterpretation. Worked examples are given to illustrate how AnCred extracts additional insight from the outcome of typical research study designs. Its ability to cast light on the use of p-values, the interpretation of non-significant findings and the so-called ‘replication crisis’ is also discussed

Use of Advanced Flexible Modeling Approaches for Survival Extrapolation from Early Follow-up Data in two Nivolumab Trials in Advanced NSCLC with Extended Follow-up

Objectives: Immuno-oncology (IO) therapies are often associated with delayed responses that are deep and durable, manifesting as long-term survival benefits in patients with metastatic cancer. Complex hazard functions arising from IO treatments may limit the accuracy of extrapolations from standard parametric models (SPMs). We evaluated the ability of flexible parametric models (FPMs) to improve survival extrapolations using data from 2 trials involving patients with non–small-cell lung cancer (NSCLC). Methods: Our analyses used consecutive database locks (DBLs) at 2-, 3-, and 5-y minimum follow-up from trials evaluating nivolumab versus docetaxel in patients with pretreated metastatic squamous (CheckMate-017) and nonsquamous (CheckMate-057) NSCLC. For each DBL, SPMs, as well as 3 FPMs—landmark response models (LRMs), mixture cure models (MCMs), and Bayesian multiparameter evidence synthesis (B-MPES)—were estimated on nivolumab overall survival (OS). The performance of each parametric model was assessed by comparing milestone restricted mean survival times (RMSTs) and survival probabilities with results obtained from externally validated SPMs. Results: For the 2- and 3-y DBLs of both trials, all models tended to underestimate 5-y OS. Predictions from nonvalidated SPMs fitted to the 2-y DBLs were highly unreliable, whereas extrapolations from FPMs were much more consistent between models fitted to successive DBLs. For CheckMate-017, in which an apparent survival plateau emerges in the 3-y DBL, MCMs fitted to this DBL estimated 5-y OS most accurately (11.6% v. 12.3% observed), and long-term predictions were similar to those from the 5-y validated SPM (20-y RMST: 30.2 v. 30.5 mo). For CheckMate-057, where there is no clear evidence of a survival plateau in the early DBLs, only B-MPES was able to accurately predict 5-y OS (14.1% v. 14.0% observed [3-y DBL]). Conclusions: We demonstrate that the use of FPMs for modeling OS in NSCLC patients from early follow-up data can yield accurate estimates for RMST observed with longer follow-up and provide similar long-term extrapolations to externally validated SPMs based on later data cuts. B-MPES generated reasonable predictions even when fitted to the 2-y DBLs of the studies, whereas MCMs were more reliant on longer-term data to estimate a plateau and therefore performed better from 3 y. Generally, LRM extrapolations were less reliable than those from alternative FPMs and validated SPMs but remained superior to nonvalidated SPMs. Our work demonstrates the potential benefits of using advanced parametric models that incorporate external data sources, such as B-MPES and MCMs, to allow for accurate evaluation of treatment clinical and cost-effectiveness from trial data with limited follow-up. Flexible advanced parametric modeling methods can provide improved survival extrapolations for immuno-oncology cost-effectiveness in health technology assessments from early clinical trial data that better anticipate extended follow-up. Advantages include leveraging additional observable trial data, the systematic integration of external data, and more detailed modeling of underlying processes. Bayesian multiparameter evidence synthesis performed particularly well, with well-matched external data. Mixture cure models also performed well but may require relatively longer follow-up to identify an emergent plateau, depending on the specific setting. Landmark response models offered marginal benefits in this scenario and may require greater numbers in each response group and/or increased follow-up to support improved extrapolation within each subgroup

An observational prospective study of topical acidified nitrite for killing methicillin-resistant Staphylococcus aureus (MRSA) in contaminated wounds

Background Endogenous nitric oxide (NO) kills bacteria and other organisms as part of the innate immune response. When nitrite is exposed to low pH, NO is generated and has been used as an NO delivery system to treat skin infections. We demonstrated eradication of MRSA carriage from wounds using a topical formulation of citric acid (4.5%) and sodium nitrite (3%) creams co-applied for 5 days to 15 wounds in an observational prospective pilot study of 8 patients. Findings Following treatment with topical citric acid and sodium nitrite, 9 of 15 wounds (60%) and 3 of 8 patients (37%) were cleared of infection. MRSA isolates from these patients were all sensitive to acidified nitrite in vitro compared to methicillin-sensitive S. aureus and a reference strain of MRSA. Conclusions Nitric oxide and acidified nitrite offer a novel therapy for control of MRSA in wounds. Wounds that were not cleared of infection may have been re-contaminated or the bioavailability of acidified nitrite impaired by local factors in the tissue

On the Importance of Countergradients for the Development of Retinotopy: Insights from a Generalised Gierer Model

During the development of the topographic map from vertebrate retina to superior colliculus (SC), EphA receptors are expressed in a gradient along the nasotemporal retinal axis. Their ligands, ephrin-As, are expressed in a gradient along the rostrocaudal axis of the SC. Countergradients of ephrin-As in the retina and EphAs in the SC are also expressed. Disruption of any of these gradients leads to mapping errors. Gierer's (1981) model, which uses well-matched pairs of gradients and countergradients to establish the mapping, can account for the formation of wild type maps, but not the double maps found in EphA knock-in experiments. I show that these maps can be explained by models, such as Gierer's (1983), which have gradients and no countergradients, together with a powerful compensatory mechanism that helps to distribute connections evenly over the target region. However, this type of model cannot explain mapping errors found when the countergradients are knocked out partially. I examine the relative importance of countergradients as against compensatory mechanisms by generalising Gierer's (1983) model so that the strength of compensation is adjustable. Either matching gradients and countergradients alone or poorly matching gradients and countergradients together with a strong compensatory mechanism are sufficient to establish an ordered mapping. With a weaker compensatory mechanism, gradients without countergradients lead to a poorer map, but the addition of countergradients improves the mapping. This model produces the double maps in simulated EphA knock-in experiments and a map consistent with the Math5 knock-out phenotype. Simulations of a set of phenotypes from the literature substantiate the finding that countergradients and compensation can be traded off against each other to give similar maps. I conclude that a successful model of retinotopy should contain countergradients and some form of compensation mechanism, but not in the strong form put forward by Gierer

Network community cluster-based analysis for the identification of potential leukemia drug targets

Leukemia is a hematologic cancer which develops in blood tissue and causes rapid generation of immature and abnormal-shaped white blood cells. It is one of the most prominent causes of death in both men and women for which there is currently not an effective treatment. For this reason, several therapeutical strategies to determine potentially relevant genetic factors are currently under development, as targeted therapies promise to be both more effective and less toxic than current chemotherapy. In this paper, we present a network community cluster-based analysis for the identification of potential gene drug targets for acute lymphoblastic leukemia and acute myeloid leukemia.Peer ReviewedPostprint (author's final draft

A randomised, open label, active comparator trial assessing the effects of 26 weeks of liraglutide or sitagliptin on cardiovascular function in young obese adults with type 2 diabetes

Aim To compare the effects of a glucagon‐like peptide‐1 receptor agonist and a dipeptidyl peptidase‐4 inhibitor on magnetic resonance imaging‐derived measures of cardiovascular function. Materials and methods In a prospective, randomized, open‐label, blinded endpoint trial liraglutide (1.8 mg) and sitagliptin (100 mg) were compared in asymptomatic, non‐insulin treated young (aged 18‐50 years) adults with obesity and type 2 diabetes. The primary outcome was difference in circumferential peak early diastolic strain rate change (PEDSR), a biomarker of cardiac diastolic dysfunction 26 weeks after randomization. Secondary outcomes included other indices of cardiac structure and function, HbA1c and body weight. Results Seventy‐six participants were randomized (54% female, mean ± SD age 44 ± 6 years, diabetes duration 4.4 years, body mass index 35.3 ± 6.1 kg m−2), of whom 65% had ≥1 cardiovascular risk factor. Sixty‐one participants had primary outcome data available. There were no statistically significant between‐group differences (intention‐to‐treat; mean [95% confidence interval]) in PEDSR change (−0.01 [−0.07, +0.06] s−1), left ventricular ejection fraction (−1.98 [−4.90, +0.94]%), left ventricular mass (+1.14 [−5.23, +7.50] g) or aortic distensibility (−0.35 [−0.98, +0.28] mmHg−1 × 10−3) after 26 weeks. Reductions in HbA1c (−4.57 [−9.10, −0.37] mmol mol−1) and body weight (−3.88 [−5.74, −2.01] kg) were greater with liraglutide. Conclusion There were no differences in cardiovascular structure or function after short‐term use of liraglutide and sitagliptin in younger adults with obesity and type 2 diabetes. Longer studies in patients with more severe cardiac dysfunction may be necessary before definitive conclusions can be made about putative pleiotropic properties of incretin‐based therapies

The transcriptional response of Caenorhabditis elegans to ivermectin exposure identifies novel genes involved in the response to reduced food intake

We have examined the transcriptional response of Caenorhabditis elegans following exposure to the anthelmintic drug ivermectin (IVM) using whole genome microarrays and real-time QPCR. Our original aim was to identify candidate molecules involved in IVM metabolism and/or excretion. For this reason the IVM tolerant strain, DA1316, was used to minimise transcriptomic changes related to the phenotype of drug exposure. However, unlike equivalent work with benzimidazole drugs, very few of the induced genes were members of xenobiotic metabolising enzyme families. Instead, the transcriptional response was dominated by genes associated with fat mobilization and fatty acid metabolism including catalase, esterase, and fatty acid CoA synthetase genes. This is consistent with the reduction in pharyngeal pumping, and consequential reduction in food intake, upon exposure of DA1316 worms to IVM. Genes with the highest fold change in response to IVM exposure, cyp-37B1, mtl-1 and scl-2, were comparably up-regulated in response to short–term food withdrawal (4 hr) independent of IVM exposure, and GFP reporter constructs confirm their expression in tissues associated with fat storage (intestine and hypodermis). These experiments have serendipitously identified novel genes involved in an early response of C. elegans to reduced food intake and may provide insight into similar processes in higher organisms

Spina bifida-predisposing heterozygous mutations in Planar Cell Polarity genes and Zic2 reduce bone mass in young mice

Fractures are a common comorbidity in children with the neural tube defect (NTD) spina bifida. Mutations in the Wnt/planar cell polarity (PCP) pathway contribute to NTDs in humans and mice, but whether this pathway independently determines bone mass is poorly understood. Here, we first confirmed that core Wnt/PCP components are expressed in osteoblasts and osteoclasts in vitro. In vivo, we performed detailed µCT comparisons of bone structure in tibiae from young male mice heterozygous for NTD-associated mutations versus WT littermates. PCP signalling disruption caused by Vangl2 (Vangl2Lp/+) or Celsr1 (Celsr1Crsh/+) mutations significantly reduced trabecular bone mass and distal tibial cortical thickness. NTD-associated mutations in non-PCP transcription factors were also investigated. Pax3 mutation (Pax3Sp2H/+) had minimal effects on bone mass. Zic2 mutation (Zic2Ku/+) significantly altered the position of the tibia/fibula junction and diminished cortical bone in the proximal tibia. Beyond these genes, we bioinformatically documented the known extent of shared genetic networks between NTDs and bone properties. 46 genes involved in neural tube closure are annotated with bone-related ontologies. These findings document shared genetic networks between spina bifida risk and bone structure, including PCP components and Zic2. Genetic variants which predispose to spina bifida may therefore independently diminish bone mass

Does physical activity counselling enhance the effects of a pedometer-based intervention over the long-term : 12-month findings from the Walking for Wellbeing in the West study

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